This Program Project focuses on Tourette's syndrome (TS) and etiologically related disorders as a model for understanding the interplay of biological and psychological factors during the course of development. TS is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) that can persist into adulthood and be chronically disabling. Although treatment regimens have been developed that benefit individuals with TS and OCD, many patients do not improve or their improvement is not sustained. Over the past two decades, notable advances, have occurred in our understanding of these conditions, including: (1) that TS and related conditions are much more common than previously recognized, affecting as many as 0.3 - 3% of the population; (2) that the natural history of these disorders is complex and dependent on age- and gender-specific factors; (3) that vulnerability to TS is mediated by both genetic and environmental factors; and (4) that specific brain regions and neurotransmitter and neuromodulator systems localized in the basal ganglia and functionally related structures are likely to provide the neurobiological substrate for TS and 0CD. The long-term objectives of this Program Project are to build on these advances using available clinical, neurobiological, genetic and epidemiological techniques and expertise to identify the causes and determinants of these conditions and to develop techniques for early detection and safe and effective treatment. This work is organized within four project areas: Genetic Factors (1), Neurobiological Substrates (II), Epigenetic and Environmental Factors (III), and Treatment Studies (IV), and will be supported by Administrative, Clinical and Data Analytic Core Resources.